A century-old drug that failed in its original intent
to treat tuberculosis but has worked well as
an antileprosy medicine now holds new promise as a
potential therapy for multiple sclerosis and other
autoimmune diseases.
"We never expected that an old antibiotic would hit
this target that has been implicated in
multiple sclerosis, psoriasis and type 1 diabetes," said
Johns Hopkins pharmacologist Jun O. Liu.
"People have been working for years and spending tens of
millions of dollars on developing a drug to
inhibit a specific molecular target involved in these
diseases, and here we have a safe, known drug that
hits that target." The target is the Kv1.3 potassium
channel.
The finding about clofazimine, a synthetic compound
made in the 1890s, is reported in Public
Library of Science by Johns Hopkins University researchers,
who uncovered the drug's latest
potential during an ongoing and exhaustive screening of
FDA-approved drugs designed to identify new
uses for them. The team was specifically hunting for
immune-system control agents within the Johns
Hopkins Drug Library, a collection assembled over the past
seven years by Liu and colleagues of more
than 3,000 drugs in pharmacies or being tested in phase II
clinical trials.
The scientists said they were surprised to discover
that clofazimine interferes with a molecular
pathway important in orchestrating the human body's immune
response.
"Until now, clofazimine's presumed target was not
human cells but bacteria," said Liu, a
professor of
pharmacology and molecular sciences in the School of
Medicine. "But we discovered the
drug has a tremendous effect on human immune cells that are
heavily involved in both the initiation
and execution of an effective immune response."
More specifically, Liu's team sought drugs that stop
the molecular signaling pathway that leads
from the surface of an immune-system cell to the cell's
interior, where the signal turns on genes
important in activating the immune response. In autoimmune
diseases, a person's own white blood cells,
meant to fight infection or disease, are misguided to the
target and attack the body's own cells,
damaging or destroying them.
To search for such compounds, the team first
engineered cells to mimic an immune cell's natural
signaling pathway, a complex and circuitous route from the
cell surface to the genetic switch inside.
They then subjected these specialized cells to the Drug
Library, one at a time, and identified more
than 200 hits — drugs that inhibited the signaling
system significantly, by more than 50 percent.
When they compared the potency of the 200 with each
other, "clofazimine was the hit with the
highest inhibitory activity," Liu said.
Next, by systematically studying the multistep
signaling process, the researchers pinpointed
clofazimine's molecular target, a protein "pore" called ion
channel Kv1.3, which plays an essential role in
the complicated signaling process. One of the key steps
involved in turning on the immune response is
the prolonged accumulation of calcium inside of immune
cells, Liu said. When the researchers
stimulated an immune cell, setting the signaling event in
motion, they noticed that lots of calcium
flushed into the cell and lingered there. However, when
they pretreated the immune cells with
clofazimine, the calcium rush was much less, and it didn't
hang around as long.
"This let us conclude that clofazimine was blocking
the calcium influx into the immune cells," Liu
said. "Without enough calcium getting inside a cell, the
signaling pathway that turns on the immune
response was short-circuited." The Johns Hopkins group also
showed that clofazimine tamps down the
presence of free calcium in immune cells by disrupting a
potassium channel. The combined effect is to
shut down a signaling pathway involved in autoimmune
disease.
In addition to Liu, authors of this paper are Yunzhao
R. Ren, Fan Pan, Curtis R. Chong, Jing Xu,
Yongjun Dang and Jin Zhang, all of Johns Hopkins; Reinhold
Penner, Suhel Parvez and Andrea Fleig, all
of the University of Hawaii; and Hongsi Jiang, of
Northwestern University.
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